1-methyl-5(2&#39;, 2&#39;-diphenyl-3&#39;-ethyl-4&#39;-furylmethyl)-imidazole and salts and lower alkyl quaternaries



United METHYL)-IMIDAZOLE AND-SALTS ALKYL QUATERNARIES Harold E. Zaugg, Lake Foresfiand" Robert W. De Net,

Waukegan, 111., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois N Drawing. Filed Dec. 29, 1958, Ser. No. 783,087

Claims. (Cl. 260-309) This invention relates to a novel alkaloid derivative, particularly, a diaryl derivative of pilocarpine. The chemical formula for pilocarpine is:

Pilocarpine contains a lactone ring which is functionally reacted with a Grignard reagent to produce a derivative thereof. The novel compound of this invention is prepared by reacting pilocarpine with a phenyl Grignard reagent to yield the glycol:

CHIOH on 1TIOH;CHCHC (0.11.), OH: 5 (I) to which is assigned the chemical name, 1-methyl-5-'(3- ethyl-4'-hydroxy-2-hydroxymethyl-4',4 diphenylbu-tyl)- imidazole. This glycol, in turn, is converted to an optically active hydrochloride salt and, thereafter, dehydrated to form the novel diphenyl tetrahydrofuran derivative:

, be formed with a variety of inorganic acids such assulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic and like acids. Strongly organic acids may also be used such as citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, cyclohexylsulfamic and related acids. The quaternary ammonium salts can be formed by the addition of alkyl'halides such as chlorides and bromides of methyl, ethyl, propyl, isopropyl, allyl and isobutyl alkyls. V

The following examples are presented to teach the preparation of the compound of this invention, but such examples are not intended to represent an exclusive embodi ment thereof.

EXAMPLE I 1methyl-5-(3'-ethyl-4'-hydr0xy-2'-hydro.xymelhyl-4',4'- diphenylbutyl) -imidazole To a'solution of phenylmagnesium bromide in ether prepared fromv 37.7 g. (0.24 mole) of bromobenzene and 5.75 g. (0.24 mole) of magnesium is added, in portions, 15 g. (0.06 mole) of powdered pilocarpine hydrochloride. The mixture is stirred and refluxed overnight and decomposed withaqueous ammonium chloride solution. The free base, insoluble in ether, is collected at the filter to give, after recrystallizationfromdry ethanol, 14.3 g. (65%) of the glycol I, M.P. 285-288 dec., and one recrystallization gives a M.P. of 291-293 dec.

Analysis.- Calcd. for C H N -O C, 75.79%; H, 7.74%; N, 7.68%. Found: C, 75.85%; H, 7.71%; N, 7.50%. The hydrochloride salt of the base of Example I is prepared from isopropyl alcohol-ether, M.P. 137-139 dec. The specific rotation, M1 of the hydrochloride is -145 (c=0.008 gL/mL; H 0).

Analysis.Calcd. for C H ClN- O C, 68.90%; H, Found: C, 68.78%; H, 7.73%; N,

EXAMPLE H I-methyl-S-(2',2'-diphenyl-3'-ethyl-4 ;furylmethyl) imidazole A solution of 3.6 g. of the glycol I in 30 ml. of glacial acetic acid containing 10 ml. of concentrated hydrochloric acid is refluxed for 2 hours. The mixture is concentrated v to dryness under reduced pressure, the residue is dissolved base is taken up in ether and dried overanhydrous mag nesium sulfate. Filtration and removal of the ether by distillation gives an'oil which cannot be crystallized. It

Y procedure of Example II is formed by dissolving said base in methyl ethyl 'ketone and adding thereto excess methyl iodide. The precipitated salt is recrystallized from ethanol and has a molecular weight of 524.5

- The foregoing examples present the selected Grignard reagent as phenylmagnesium' bromide. However, it is apparent to those skilled in the art that phenylmagnesium halides other than the bromide are operable to prepare the novel tetrahydrofuran form of pilocarpine.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

We claim:

1. 1-methyl-5-(2,2'-diphenyl 3-ethyl-4'-furylmethy1)- imidazole.

2. 1-methyl-5-(2',2'-diphenyl 3'-ethyl-4'-furylmethyl)- imidazole hydrochloride.

- 3. 1-methyl-5-(2,2-diphenyl 3'-ethyl-4'-furylmethyl)- imidazole monomethiodide.

,4. A compound selected from :5 r To? I 2,946,803

the mom-toxic acid addition-salts thereof and the mm which comprises adding the compound: toxic loweralkyl quaternary ammonium salt thereof.

5. A process for preparing a compound selected from H: H the class consisting of bases of the formula: I I

5 0H. t Y. can. to a mixture of about three parts glacial acetic acid and O\ a I aboubone part oficonccntrated hydrochloric'acid anus- I 1 3 fluxing'theresuhingmixture for abouttwo hour's. N --OH: 7 10 

4. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA: 